| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Subjects with red blood cell (RBC) transfusion dependent β-thalassemia major and β thalassemia intermedia, as well as non-transfusion dependent β-thalassemia intermedia will take part in this study. |
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| E.1.1.1 | Medical condition in easily understood language |
| Red blood cell (RBC) transfusion-dependent beta-thalassemia and non-transfusion dependent beta-thalassemia |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10062923 |
| E.1.2 | Term | Thalassemia intermedia |
| E.1.2 | System Organ Class | 100000004850 |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10054661 |
| E.1.2 | Term | Thalassemia major |
| E.1.2 | System Organ Class | 100000004850 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10054660 |
| E.1.2 | Term | Thalassemia beta |
| E.1.2 | System Organ Class | 100000004850 |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To determine a safe, tolerable and effective dose of sotatercept in adult subjects with RBC transfusion-dependent beta-thalassemia major (including all subtypes)and β thalassemia intermedia, as well as non-transfusion dependent β-thalassemia intermedia. |
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| E.2.2 | Secondary objectives of the trial |
•To assess the reduction in transfusion burden in transfusion dependent β-thalassemia major and intermedia subjects
•To assess the Hgb level increase from baseline in non-transfusion dependent β-thalassemia intermedia subjects.
• To evaluate the safety profile of sotatercept in adult subjects with RBC transfusion-dependent beta-thalassemia major and intermedia, as well as in adult subjects with non-transfusion dependent β-thalassemia intermedia
•To assess the pharmacokinetics (PK) of sotatercept in adult subjects with RBC transfusion-dependent beta-thalassemia major and intermedia, as well as in adult subjects with non-transfusion dependent β-thalassemia intermedia
•To assess the immunogenicity of sotatercept in adult subjects with RBC transfusion-dependent beta-thalassemia major and intermedia as well as in adult subjects with non-transfusion dependent β-thalassemia intermedia
•To evaluate the change in Quality of Life from baseline in subjects enrolled in the Expansion Cohort. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Men and women ≥ 18 years of age at the time of signing the informed consent document with a diagnosis of β-thalassemia major (including all subtypes) or β-thalassemia intermedia.
2.For transfusion dependent subjects: permanent transfusion dependency is defined as requiring packed red blood cells (pRBCs) and iron chelation therapy:
•Average transfusion requirement of at least 2 units per 30 days of pRBCs (Gale, 2011) confirmed for a minimum of 168 days (six months) immediately preceding enrollment (Day 1);
•No transfusion-free period of more than 45 consecutive days during the 168 days immediately preceding enrollment;
•Mean Prior transfusion hemoglobin levels ≤ 10.5 g/dL.
3.For non-transfusion dependent subjects: non-transfusion dependency is defined as transfusion free, with the exception of ≤ one episode of transfusion in the period of a minimum of 168 days immediately preceding enrollment (One episode of transfusion is defined as ≤ 4 transfusion units administered, occurring within 168 days immediately preceding enrollment due to concurrent illness [e.g. infection], [Guidelines Clin Management of Thalassaemia, 2008]).
4.Performance status: ECOG score of 0 to 1.
5.No concurrent severe hepatic disease:
•AST or ALT no greater than 3 x upper limit of normal (ULN);
•Albumin ≥ 3 g/dL.
6.Serum creatinine ≤ 1.5 x ULN and creatinine clearance > 60 mL/min.
7.Females of childbearing potential participating in the study are to use highly effective methods of birth control during study participation and for 112 days (approximately five times the mean terminal half-life of sotatercept [23 days] based on multiple-dose PK data) following the last dose of sotatercept. FCBP must have a negative serum beta-human chorionic gonadotropin (β-HCG) pregnancy test within three days of sotatercept dosing (Day 1). Subjects must be counseled concerning measures to be used to prevent pregnancy and potential toxicities prior to the first dose of sotatercept. A FCBP is a sexually mature woman who has not undergone a hysterectomy or bilateral oophorectomy or who has not been postmenopausal for at least 24 consecutive months (i.e., who has had menses at some time in the preceding 24 months).
8.Males must agree to use a latex condom during any sexual contact with FCBSs while participating in the study and for 112 days following the last dose of sotatercept, even if he has undergone a successful vasectomy. Subjects must be counseled concerning measures to be used to prevent pregnancy and potential toxicities prior to the first dose of sotatercept.
9.Agreement to adhere to the study visit schedule, understand and comply with all protocol requirements.
10. Understand and provide written informed consent.
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| E.4 | Principal exclusion criteria |
1.Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing participating in the study.
2.Evidence of active hepatitis C (HCV) infection, or active infectious hepatitis B, or known positive for human immunodeficiency virus (HIV).
3.Known history of thromboembolic events ≥ Grade 3 according to NCI CTCAE version 4.0 (current active minor version)
4. Subjects with insulin dependent diabetes
5. Subjects with major cardiac problems such as:
•Major risk of heart failure
•Cardiac arrhythmia which requires treatment (i.e atrial fibrillation)
6. Treatment with another investigational drug or device < 28 days prior to study entry as well as any prior exposure to sotatercept.
7.Use of an erythropoiesis stimulating agent (ESA) within the 28 days prior to enrollment (study Day 1).
8.Subjects on hydroxyurea treatment for which the dose was changed in the last one year prior to subject enrollment.
9. Subjects on longterm anticoagulant therapy, such as heparin or warfarin
10. Subjects who started bisphosphonates within the last three months prior to subject enrollment
11.Pregnant or lactating females.
12.Uncontrolled hypertension. Controlled hypertension for this protocol is considered ≤ Grade 1 according to NCI CTCAE version 4.0 (current active minor version).
13.A history of major organ damage including:
•Liver disease with ALT > 3x ULN or histopathological evidence of liver cirrhosis on liver biopsy;
•Heart disease with ejection fraction ≥ Grade 2 according to NCI CTCAE version 4.0 (current active minor version);
•Kidney disease with a calculated creatinine clearance < 40 mL/min (Cockcroft-Gault formula);
•Pulmonary fibrosis or pulmonary hypertension confirmed by a specialist.
14.Adrenal insufficiency.
15.Heart failure as classified by the New York Heart Association (NYHA) classification of 3 or higher (Appendix C).
16.Major surgery within 30 days prior to study Day 1 (subjects must have completely recovered from any previous surgery prior to study Day 1).
17. History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the investigational product (see Investigator Brochure)
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Potential recommended dose (PRD) and actual recommended dose (ARD). |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
ARD will be evaluated following the last subject of the confirmation cohort, including the last subject who received the last dose.
PRD will be evaluated for each dose level/subject cohort (n=6) after the last patient received the 3rd dose +delays.
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|
| E.5.2 | Secondary end point(s) |
•RBC transfusion burden reduction in transfusion dependent β-thalassemia major and β-thalassemia intermedia subjects.
•Hgb level increase during the study treatment compared to the baseline Hgb level in non-transfusion dependent β-thalassemia intermedia subjects
•Safety (type, frequency, and severity of adverse events and relationship to sotatercept [according to the currently active minor version of National Cancer Institute (NCI) Common Terminology for Adverse Events (CTCAE) version 4.0]).
•Concentrations of sotatercept in serum.
•Concentration of anti sotatercept antibody.
•Quality of Life (QoL) change from baseline in subjects enrolled in the Expansion
Cohort. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
•RBC transfusion burden reduction-assessed at every visit
•Hg level increase-assessed at every visit
•Safety-assessed continuously if safety concern between visits, otherwise at every visit, 3weeks after last dose, 1,2,3&4 months after last dose
•Concentrations of sotatercept in serum-every visit during 1st cycle (Dose 1), Day 1&8 of Doses 2&3, every Day 1 of Doses 4 to 6, Day1 visit every 3 dose up to max 22months of treatment, at treatment discontinuation visit, 1,2,3&4 months after last dose
•Concentration of anti–sotatercept antibody-every Day 1 of each Dose up to Dose 6, Day 1visit every 3 dose up to max of 22 months of treatment, 2&4 months after last dose
•QoL-evaluated at Day 168 & 336 after Dose 1 Day 1, independent of Dose Delay for subjects enrolled in Expansion Cohort only |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Dose-finding, tolerability and immunogeneicity study |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 6 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 7 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| is defined as either the date of last visit of the last subject to complete the Post-Treatment Follow-Up Period, or the date of receipt of the last data point from the last subject that is required for primary, secondary and/or exploratory analysis, as pre-specified in the protocol, whichever is the later date |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 10 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 10 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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